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Ischemia reperfusion injury (IRI) during liver transplantation increases morbidity and contributes to allograft dysfunction. There are no therapeutic strategies to mitigate IRI. We examined a novel hypothesis: caspase 1 and caspase 11 serve as danger-associated molecular pattern (DAMPs) sensors in IRI. By performing microarray analysis and using caspase 1/caspase 11 double-knockout (Casp DKO) mice, we show that the canonical and non-canonical inflammasome regulators are upregulated in mouse liver IRI. Ischemic pre (IPC)- and post-conditioning (IPO) induce upregulation of the canonical and non-canonical inflammasome regulators. Trained immunity (TI) regulators are upregulated in IPC and IPO. Furthermore, caspase 1 is activated during liver IRI, and Casp DKO attenuates liver IRI. Casp DKO maintained normal liver histology via decreased DNA damage. Finally, the decreased TUNEL assay-detected DNA damage is the underlying histopathological and molecular mechanisms of attenuated liver pyroptosis and IRI. In summary, liver IRI induces the upregulation of canonical and non-canonical inflammasomes and TI enzyme pathways. Casp DKO attenuate liver IRI. Development of novel therapeutics targeting caspase 1/caspase 11 and TI may help mitigate injury secondary to IRI. Our findings have provided novel insights on the roles of caspase 1, caspase 11, and inflammasome in sensing IRI derived DAMPs and TI-promoted IRI-induced liver injury.

Background: Since February 2020, exception points have been allocated equivalent to the median model for end-stage liver disease at transplant within 250 nautical miles of the transplant center (MMaT/250). We compared transplant rate and waitlist mortality for hepatocellular carcinoma (HCC) exception, non-HCC exception, and non-exception candidates to determine whether MMaT/250 advantages (or disadvantages) exception candidates., Methods: Using Scientific Registry of Transplant Recipients data, we identified 23 686 adult, first-time, active, deceased donor liver transplant (DDLT) candidates between February 4, 2020, and February 3, 2022. We compared DDLT rates using Cox regression, and waitlist mortality/dropout using competing risks regression in non-exception versus HCC versus non-HCC candidates., Results: Within 24 mo of study entry, 58.4% of non-exception candidates received DDLT, compared with 57.8% for HCC candidates and 70.5% for non-HCC candidates. After adjustment, HCC candidates had 27% lower DDLT rate (adjusted hazard ratio =  0.68 0.73 0.77 ) compared with non-exception candidates. However, waitlist mortality for HCC was comparable to non-exception candidates (adjusted subhazard ratio [asHR] =  0.93 1.03 1.15 ). Non-HCC candidates with pulmonary complications of cirrhosis or cholangiocarcinoma had substantially higher risk of waitlist mortality compared with non-exception candidates (asHR =  1.27 1.70 2.29 for pulmonary complications of cirrhosis, 1.35 2.04 3.07 for cholangiocarcinoma). The same was not true of non-HCC candidates with exceptions for other reasons (asHR =  0.54 0.88 1.44 )., Conclusions: Under MMaT/250, HCC, and non-exception candidates have comparable risks of dying before receiving liver transplant, despite lower transplant rates for HCC. However, non-HCC candidates with pulmonary complications of cirrhosis or cholangiocarcinoma have substantially higher risk of dying before receiving liver transplant; these candidates may merit increased allocation priority., Competing Interests: This work was supported by grants R01DK132395 (A.B.M.) from the National Institute of Diabetes and Digestive and Kidney Diseases and K24AI144954 (D.S.) from the National Institute of Allergy and Infectious Diseases. The other authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Pediatric (age < 18 years) kidney transplant (KT) candidates face increasingly complex choices. The 2014 kidney allocation system nearly doubled wait times for pediatric recipients. Given longer wait times and new ways to optimize compatibility, more pediatric candidates may consider kidney-paired donation (KPD). Motivated by this shift and the potential impact of innovations in KPD practice, we studied pediatric KPD procedures in the US from 2008 to 2021., Methods: We describe the characteristics and outcomes of pediatric KPD recipients with comparison to pediatric non-KPD living donor kidney transplants (LDKT), pediatric LDKT recipients, and pediatric deceased donor (DDKT) recipients., Results: Our study cohort includes 4987 pediatric DDKTs, 3447 pediatric non-KPD LDKTs, and 258 pediatric KPD transplants. Fewer centers conducted at least one pediatric KPD procedure compared to those that conducted at least one pediatric LDKT or DDKT procedure (67, 136, and 155 centers, respectively). Five centers performed 31% of the pediatric KPD transplants. After adjustment, there were no differences in graft failure or mortality comparing KPD recipients to non-KPD LDKT, LDKT, or DDKT recipients., Discussion: We did not observe differences in transplant outcomes comparing pediatric KPD recipients to controls. Considering these results, KPD may be underutilized for pediatric recipients. Pediatric KT centers should consider including KPD in KT candidate education. Further research will be necessary to develop tools that could aid clinicians and families considering the time horizon for future KT procedures, candidate disease and histocompatibility characteristics, and other factors including logistics and donor protections., (© 2023 The Authors. Pediatric Transplantation published by Wiley Periodicals LLC.)

Introduction: This study identifies the effect of individual donor and recipient characteristics on graft survival in living-donor kidney transplantation (LDKT) using a recently described novel measure, kidney life years (KLYs)., Materials and Methods: The Organ Procurement and Transplantation Network/United Network for Organ Sharing database was used to identify first-time kidney-only LDKT recipients between 1987 and 2020 who did not experience death with a functioning graft (DWFG) and were not missing relevant information (n = 87,290). Patient characteristics were evaluated using Cox and multiple regression analyses, with the dependent variable being KLYs. An equation for expected KLYs based on patient characteristics was created using regression coefficients. The equation was validated using bootstrapped Pearson correlations and then applied to the DWFG group for comparison., Results: Based on statistical significance from Cox and multiple linear regression analyses, 9 of the original 18 variables were selected for inclusion in the equation. Variables with notable impact included HLA match points (0.021 KLYs; 95% CI: [0.019,0.024]; P ≤ .001), Donor Age (-0.030 KLYs; 95% CI: [-0.035,-0.025]; P ≤ .001), and Donor African American Ethnicity (-2.356 KLYs; 95% CI: [-2.552,-2.159]; P ≤ .001). Equation validation was supported, given a negative correlation (r = -0.071; P ≤ .001) between expected KLY change and observed graft failure. Expected KLY change was found to be greater in those who eventually DWFG when compared with all other LDKTs (t = -5.735, P ≤ .001)., Conclusions: Increasing HLA match points may be more beneficial for graft longevity than minimizing donor age in comparisons using realistic between-donor differences. Additionally, greater average expected KLYs in those who ultimately DWFG may illustrate an opportunity for improved donor-recipient matching., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Kidney transplant patients have a higher risk of renal cell carcinoma (RCC) compared to non-transplanted end-stage kidney disease (ESKD) patients. This increased risk has largely been associated with the use of immunosuppression; however, recent genetic research highlights the significance of tissue specificity in cancer driver genes. The implication of tissue specificity becomes more obscure when addressing transplant patients, as two distinct metabolic environments are present within one individual. The oncogenic potential of donor renal tissue is largely unknown but assumed to pose minimal risk to the kidney transplant recipient (KTR). Our review challenges this notion by examining how donor and recipient microenvironments impact a transplant recipient's associated risk of renal cell carcinoma. In doing so, we attempt to encapsulate how ESKD-RCC and KTR-RCC differ in their incidence, pathogenesis, outcome, and approach to management.

Background: Tacrolimus extended-release tablets have been Food and Drug Administration-approved for use in the de novo kidney transplant population. Dosing requi rements often vary for tacrolimus based on several factors including variation in metabolism based on CYP3A5 expression. Patients who express CYP3A5 often require higher dosing of immediate-release tacrolimus, but this has not been established for tacrolimus extended-release tablets in the de novo setting., Aim: To obtain target trough concentrations of extended-release tacrolimus in de novo kidney transplant recipients according to CYP3A5 genotype., Methods: Single-arm, prospective, single-center, open-label, observational study (ClinicalTrials.gov: NCT037 13645). Life cycle pharma tacrolimus (LCPT) orally once daily at a starting dose of 0.13 mg/kg/day based on actual body weight. If weight is more than 120% of ideal body weight, an adjusted body weight was used. LCPT dose was adjusted to maintain tacrolimus trough concentrations of 8-10 ng/mL. Pharmacogenetic analysis of CYP3A5 genotype was performed at study conclusion., Results: Mean time to therapeutic tacrolimus trough concentration was longer in CYP3A5 intermediate and extensive metabolizers vs CYP3A5 non-expressers (6 d vs 13.5 d vs 4.5 d; P = 0.025). Mean tacrolimus doses and weight-based doses to achieve therapeutic concentration were higher in CYP3A5 intermediate and extensive metabolizers vs CYP3A5 non-expressers (16 mg vs 16 mg vs 12 mg; P = 0.010) (0.20 mg/kg vs 0.19 mg/kg vs 0.13 mg/kg; P = 0.018). CYP3A5 extensive metabolizers experienced lower mean tacrolimus trough concentrations throughout the study period compared to CYP3A5 intermediate metabolizers and non-expressers (7.98 ng/mL vs 9.18 ng/mL vs 10.78 ng/mL; P = 0 0.008). No differences were identified with regards to kidney graft function at 30-d post-transplant. Serious adverse events were reported for 13 (36%) patients., Conclusion: Expression of CYP3A5 leads to higher starting doses and incremental dosage titration of extended-release tacro limus to achieve target trough concentrations. We suggest a higher starting dose of 0.2 mg/kg/d for CYP3A5 expressers., Competing Interests: Conflict-of-interest statement: Adam Diamond serves as an active member of the Veloxis Pharmaceuticals Speaker’s Bureau (honoraria provided)., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Since 1995, rates of end-stage renal disease have risen dramatically in patients living with HIV infection. However, given the concern for higher rates of acute rejection in this patient population, the immunologic threat posed by HIV infection is a specter clinicians must continually confront. Living donor transplantation may negate this risk; this study aims to assess the benefit of living donor transplantation in this population and to ascertain the immunologic risk faced by patients who are HIV-infected. The 2021 UNOS database was queried, and all HIV-infected kidney transplant recipients since 1987 were identified. Recipients were stratified based on deceased (DDKT) vs living (LDKT) donor status. Overall survival, allograft survival, acute rejection, panel reactive antibody (PRA) percentage, and crossmatch positivity were compared between groups. One thousand two hundred twenty-six patients underwent DDKT, and 304 patients underwent LDKT. Living donor kidney transplantation demonstrated greater overall survival (P = .045) and graft survival (P < .001). However, no difference in acute rejection was noted between the cohorts, and no difference in overall or graft survival was evident based on PRA percentage. Crossmatch positive status did not negatively affect graft survival. Patients with HIV undergoing LDKT fared better than those undergoing DDKT. Nevertheless, patients at higher immunologic risk-elevated PRA% and crossmatch positivity-did not experience graft loss at a higher rate than patients at lower immunologic risk. These results were valid in both DDKT and LDKT cohorts. These findings suggest that infection with HIV does not overtly increase patients' immunologic risk, and concerns surrounding transplantation in this population may be overestimated., Competing Interests: Declaration of Competing Interest All the authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Nephrotoxicity is a significant side effect of thoracic transplantation. Many lung transplant patients will require subsequent renal transplantation (KAL). Recently, simultaneous lung/kidney transplants (SLuK) have become an attractive option for patients with end-stage renal disease at the time of lung transplantation. This article explores SLuK outcomes compared to conventional KAL, as well as outcomes among KAL patients against those were KAL listed but never transplanted., Materials and Methods: The United Network for Organ Sharing/the Organ Procurement and Transportation Network database was used to identify SLuK patients (n = 74), KAL transplants (n = 456), and patients who were listed for KAL but were never transplanted (n = 626). Significance was determined by chi 2 , Wilcoxon rank sum test, or independent t-tests. Death-censored graft survival for subgroups was estimated using Kaplan-Meier with log-rank for significance. Analyses were completed using SPSS Statistics 28., Results: The SLuK cohort was older (P = 0.04), more likely diabetic (P < 0.001), and had shorter life expectancies (P < 0.001) than KAL patients. Of those SLuK transplants within 5 y, 84% of patients were alive 1 y post transplant and 82% were alive 3 y post-transplant (compared to 74.6% and 60.3% of overall SLuK). Patients who did undergo KAL were younger and had a lower body mass index (both P < 0.001) compared to those who did not. Those who received a kidney had increased survival times compared to WL patients (P < 0.001)., Conclusions: Conventional KAL transplants are still favorable for average lung recipients. However, recent improvements have made SLuK an option for patients with renal dysfunction. Those patients who were able to receive KAL transplants were better surgical candidates than those who remained on the waitlist., (Copyright © 2022 Elsevier Inc. All rights reserved.)

G-protein coupled receptor (GPCR) kinase 2 (GRK2) is upregulated in heart failure (HF) patients and mouse models of cardiac disease. GRK2 is a regulator of β-adrenergic receptors (βARs), a GPCR involved in ionotropic and chronotropic responses. We and others have recently reported GRK2 to be localized in the mitochondria, although its function in the mitochondria and/or metabolism remain not clearly defined. We hypothesized that upregulation of GRK2 reduced mitochondrial respiratory function and responses to βAR activation. Utilizing isolated mouse primary adult cardiomyocytes (ACMs), we investigated the role of glucose, palmitate, ketone bodies, and BCAAs in mediating cell survival. Our results showed that myocyte upregulation of GRK2 promotes palmitate-induced cell death. Isotopologue labeling and mass spectrometry showed that the upregulation of GRK2 reduces β-hydroxybutyryl CoA generation. Next, using isoproterenol (ISO), a non-selective βAR-agonist, we determined mitochondrial function in mouse and human primary ACMs. Upregulation of GRK2 impaired ISO-mediated mitochondrial functional responses, which we propose is important for metabolic adaptations in pathological conditions. Increased cardiac levels of GRK2 reduced fatty acid-specific catabolic pathways and impaired ISO-stimulated mitochondrial function. Our data support the notion that GRK2 participates in bioenergetic remodeling and may be an important avenue for the development of novel pharmacological strategies in HF.

Introduction: Immunosuppression following kidney transplantation increases risk of BK polyomavirus reactivation, a common cause of graft dysfunction and failure. Subsequent retransplantation is a viable option that has not been extensively studied. This study further characterizes BK Virus Nephropathy (BKVN) and retransplantation in the most expansive population to date, geographically, temporally, and in magnitude., Materials and Methods: The OPTN/UNOS database was used to identify patients who received kidney or kidney-pancreas transplantation between 1987 and 2018 that resulted in BKVN-attributed failure (n = 1587). This population was divided into those who underwent retransplantation (n = 495) and those who did not (n = 1092)., Results: The retransplanted cohort was younger (45 vs. 53 yr; P<0.0001) and had fewer prior kidney transplants (P<0.003), lower expected post-transplant survival (P<0.001), lower rates of delayed graft function (DGF) (14.1% vs. 22.2%; P=0.0008), a greater proportion of white patients (55.4% vs. 43.2%; P=0.0002), a greater proportion of living donors (35.8% vs. 23.0%; P<0.0001), and longer allograft lifespan (2.95 vs. 2.41 yr; P<0.0001), compared to those not retransplanted. Among retransplants, DGF and high kidney donor profile index (KDPI) were associated with decreased allograft lifespan (P=0.001, P=0.0005, respectively). Steroid induction had no effect on allograft lifespan when compared to steroid-free regimens (P=0.915). Retransplanted allografts lasted longer than previous BKVN-failed grafts (10.44 and 3.70 years, respectively; P<0.0001)., Conclusions: Retransplantation following BKVN-associated graft failure has been associated with favorable outcomes. To maximize allograft lifespan in retransplantation, clinicians may consider selection of low KDPI donors, prevention of delayed graft function, and tailored immunosuppressive regimens that minimize steroids., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: A Domino Liver Transplant (DLT) is a successfully validated surgical option for a subset of patients awaiting liver transplant. Increased utilization of DLTs could increase the donor organ pool. However, DLTs occur primarily at a small number of high volume centers, and are rarely performed at lower volume transplant centers. This study compares DLT recipient performance outcomes between high frequency DLT centers and low frequency DLT centers., Methods: The UNOS/OPTN STAR database was queried for DLTs performed at transplant centers between 1996-2018. 193 patients were identified and categorized into high (>5 DLTs) or low (≤5 DLTs) frequency centers. Our primary endpoint was allograft survival. Our secondary endpoints were graft status at last follow up and mortality secondary to cardiac, renal, or respiratory failure., Results: Overall median allograft survival between high and low volume DLT centers was similar (48.2 months versus 42.7 months, P >0.314). The one-year (82% versus 76%), three-year (57% versus 56%), and five-year (45% versus 43%) survival percentages were also similar between the high and low volume DLT centers respectively. Overall mortality from cardiac (high 4% versus low 1.7%), renal (high 0.8% versus low 1.7%), or respiratory failure (high 0.8% versus low 1.7%) was similarly low in both groups., Conclusion: Low volume and high volume DLT centers are associated with similar outcomes of allograft survival and mortality. DLTs should be utilized more frequently, when the criteria are met, including in centers with limited experience, to expand the donor pool, decrease time on the waitlist, and improve overall survival., (Copyright © 2021. Published by Elsevier Inc.)

Background: Current guidelines recommend laparoscopic cholecystectomy be offered for patients with acute cholecystitis except those deemed as high risk. Few studies have examined the impact of frailty on outcomes for patients undergoing laparoscopic cholecystectomy. Therefore, the aim of this study was to determine the association of frailty with postoperative morbidity and mortality in patients undergoing laparoscopic cholecystectomy for acute cholecystitis., Methods: Patients undergoing laparoscopic cholecystectomy for acute cholecystectomy were identified from 2005 to 2010 in the American College of Surgeons National Surgical Quality Improvement Project (NSQIP). The Modified Frailty Index (mFI) was used a surrogate for frailty, and patients were stratified as non-frail (mFI 0), low frailty (mFI 1-2), intermediate frailty (mFI 3-4) and high frailty (mFI ≥ 5). Univariable and multivariable analyses were performed. Receiver operator curves (ROC) and an area under the curve (AUC) were generated to determine accuracy of mFI in predicting postoperative morbidity and mortality., Results: Of the 6898 patients undergoing laparoscopic cholecystectomy, 3245 (47%) patients were non-frail. There were 2913 (42%) patients with low-frailty, 649 (9%) patients with intermediate frailty, and 91 (2%) with high frailty. Clavien IV complications were higher for intermediate frail patients (OR 1.81, 95% CI 1.00-3.28, p = 0.050) and high-frail patients (OR 4.59, 95% CI 1.98-10.7, p < 0.001). Additionally, mortality was higher for patients with intermediate frailty (OR 4.69, 95% CI 1.37-16.0, p = 0.014) and high frailty (OR 12.2, 95% CI 2.67-55.5, p = 0.001). The mFI had excellent accuracy for mortality (AUC = 0.83) and Clavien IV complications (AUC = 0.73)., Conclusion: Frailty is associated with postoperative morbidity and mortality in patients undergoing laparoscopic cholecystectomy for acute cholecystitis.

Research efforts in the twenty-first century have been paramount to the discovery and development of novel pharmacological treatments in a variety of diseases resulting in improved life expectancy. Yet, cardiac disease remains a leading cause of morbidity and mortality worldwide. Over time, there has been an expansion in conditions such as atrial fibrillation (AF) and heart failure (HF). Although past research has elucidated specific pathways that participate in the development of distinct cardiac pathologies, the exact mechanisms of action leading to disease remain to be fully characterized. Protein turnover and cellular bioenergetics are integral components of cardiac diseases, highlighting the importance of mitochondria and endoplasmic reticulum (ER) in driving cellular homeostasis. More specifically, the interactions between mitochondria and ER are crucial to calcium signaling, apoptosis induction, autophagy, and lipid biosynthesis. Here, we summarize mitochondrial and ER functions and physical interactions in healthy physiological states. We then transition to perturbations that occur in response to pathophysiological challenges and how this alters mitochondrial-ER and other intracellular organelle interactions. Finally, we discuss lifestyle interventions and innovative therapeutic targets that may be used to restore beneficial mitochondrial and ER interactions, thereby improving cardiac function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Kumar, Lackey, Snyder, Karhadkar, Rao, DiCarlo and Sato.)

Fibrosis refers to the accumulation of excess extracellular matrix (ECM) components and represents a key feature of many chronic inflammatory diseases. Unfortunately, no currently available treatments specifically target this important pathogenic mechanism. MicroRNAs (miRNAs) are short, non-coding RNAs that post-transcriptionally repress target gene expression and the development of miRNA-based therapeutics is being actively pursued for a diverse array of diseases. Because a single miRNA can target multiple genes, often within the same pathway, variations in the level of individual miRNAs can potently influence disease phenotypes. Members of the miR-29 family, which include miR-29a, miR-29b and miR-29c, are strong inhibitors of ECM synthesis and fibrosis-associated decreases in miR-29 have been reported in multiple organs. We observed downregulation of miR-29a/b/c in fibrotic livers of carbon tetrachloride (CCl4) treated mice as well as in isolated human hepatocytes exposed to the pro-fibrotic cytokine TGF-β. Importantly, we demonstrate that a single systemic injection of a miR-29a expressing adeno-associated virus (AAV) can prevent and even reverse histologic and biochemical evidence of fibrosis despite continued exposure to CCl4. The observed therapeutic benefits were associated with AAV transduction of hepatocytes but not hepatic stellate cells, which are the main ECM producing cells in fibroproliferative liver diseases. Our data therefore demonstrate that delivery of miR-29 to the hepatic parenchyma using a clinically relevant gene delivery platform protects injured livers against fibrosis and, given the consistent fibrosis-associated downregulation of miR-29, suggests AAV-miR-29 based therapies may be effective in treating a variety of fibroproliferative disorders.

Kidney transplantation (KT) recipients with donor specific HLA antibodies (DSA) encounter higher rates of acute rejection and inferior allograft survival. We report our single center experience with prospective DSA monitoring and provide details of treatments utilized to overcome the potential impact of DSA in a cohort of predominantly African American adult KT recipients. Seventy-five flow crossmatch negative KT recipients underwent periodic screening for DSA utilizing the single antigen bead assay at 3, 6, 9, and 12 months post-transplant. Allograft biopsies were performed in the presence of DSA and/or evidence of graft dysfunction. The incidence of DSA was 23%, with a predominance of Class II antibodies. The rate of rejection was 6 times higher in DSA positive KT recipients compared to DSA negative patients (41% versus 7%, p = 0.004). In the DSA positive group, rejections occurred exclusively in the presence of de novo DSA and were predominantly antibody-mediated or mixed rejections. Despite a higher incidence of rejection in KT recipients with DSA, there were no significant differences in serum creatinine, graft survival, and patient survival between DSA positive and negative recipients at median follow-up of 18 months. DSA positive patients had significantly higher proteinuria compared to DSA negative recipients at 6 months, 1 year, and 3 years of follow-up. In conclusion, the detrimental effects of DSA on allograft function could be mitigated by serial DSA surveillance, protocol biopsies, and alterations in immunosuppression. With these measures, the improvement in graft survival in DSA positive KT recipients, at least at short-term, is encouraging.